The glucagon suppressing agent, somatostatin, has permitted elucidation of glucagon's contribution to diabetes, a disease in which we had uniformly found hyperglucagonemia. When we suppressed glucagon with somatostatin, hyperglycemia didn't occur--even in the total absence of insulin. When we restored glucagon to normal by giving small doses of exogenous glucagon with somatostatin, then hyperglycemia appeared as in other forms of insulin deficiency, suggesting that glucagon was an essential component of endogenous hyperglycemia, causing glucose overproduction. Even in totally depancreatized animals it was possible to prevent endogenous hyperglycemia by suppressing extrapancreatic glucagon secretion by infusing somatostatin. We identified in crude extracts of hog duodenum, in addition to GLI, a glucagon-like polypeptide which clearly is a different substance than pancreatic glucagon, a polypeptide which resembled glucagon with respect to molecular size, isoelectric point, immunologic behavior, affinity for isolated rat liver membrane, ability to activate adenylate cyclase, its glycogenolytic activity, and in collaboration with Dr. Orci's group, found in the fundus and corpus of the dog stomach and of the human duodenum cells which were morphologically and immunocytochemically indistinguishable from pancreatic A-cells, and clearly the extrapancreatic source of glucagon. We found that normal glucose concentrations could be maintained in the absence of the pancreas and of measurable plasma levels of insulin, and that in insulin-deprived dogs with long-standing alloxan diabetes, plasma glucose could be lowered merely by suppressing glucagon. These studies led to the hypothesis of the essential role of glucagon in diabetes mellitus. We have now begun studies to test the essentiality of glucagon in human diabetes mellitus to determine if it is a primary defect of diabetes independent of insulin lack and if, by therapeutic glucagon suppression, one can ameliorate the metabolic and vascular manifestations of the disease.